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Abstract

Background

Five of 7 (71%) elderly immunocompetent patients with cytomegalovirus retinitis had
retinal arteriolar occlusions versus 2 of 8 (25%) elderly immunocompromised patients
and 1 of 19 (5%) younger HIV-infected patients. Compared to HIV-infected patients,
elderly patients were more likely to have occlusive events, neovascularization or
hemorrhage, and underlying vasculopathy. The purpose of this study is to report the
novel finding of extensive retinal arteriolar occlusions and neovascularization in
immunocompetent patients with cytomegalovirus retinitis. This is a retrospective observational
cohort study of cytomegalovirus retinitis (CMVR) in a university setting. Seven patients
were elderly but not immunocompromised, 8 were elderly and iatrogenically immunocompromised,
and 16 were HIV-infected. All patients underwent polymerase chain reaction testing
of intraocular fluid. Primary outcome measure was visual acuity. Secondary outcome
measures were vascular occlusions, ischemic complications, and response to treatment.

Results

Mean age was 73, 70, and 41 years for immunocompetent, immunocompromised, and HIV-infected
patients, respectively. Diabetes and vascular disease were common in the elderly.
Vision loss to less than 5/200 occurred in 50% of the immunocompetent elderly patients,
and 17% of CMV eyes in immunocompromised and HIV patients. Occlusion of the entire
retinal vasculature occurred in 4/7 (57%) of immunocompetent patients despite lack
of Zone I involvement, and rubeosis occurred in three, disc neovascularization in
one, and vitreous hemorrhage in two patients. Vascular occlusive events were less
common in immunocompromised patients and rare in the HIV-infected.

Keywords:

Background

Cytomegaloviral infection is common. Seroprevalence increases steadily in the USA
from 36.3% in 6 to 11-year-olds to 90.8% of those aged 90 or older [1]. The most common ocular manifestation of cytomegalovirus infection is cytomegalovirus
retinitis (CMVR), which typically occurs as a resurgent infection in a latently infected
host who is severely immunocompromised by HIV infection, chemotherapy, or organ transplantation.
CMVR can also rarely present in the elderly or in other minimally compromised individuals
as an atypical acute retinal necrosis (ARN) [2-4]. Recognition of cytomegalovirus infection is important as specific anti-CMV treatments
rather than the anti-viral agents used for other herpes class viruses are required
to control the infection.

We present cases of CMVR in 15 elderly, non-HIV-infected adults in order to facilitate
clinical recognition and to expand the current literature. Eight of the 19 affected
eyes had devastating visual outcomes after delays in diagnosis; in 5 of the 8 eyes,
this was due to retinal arteriolar occlusion, a previously under-recognized complication
of CMVR. The frequency of retinal vascular occlusion was much higher than in younger
HIV-infected patients with CMVR.

Results

Fifteen patients age 60 and older were identified who were not HIV-infected and had
a diagnosis of CMVR after diagnostic PCR testing. Seven, with an average age of 73
± 7.4 years, were judged to be immunocompetent. Of these, one was taking low doses
of oral corticosteroids for healed giant cell arteritis, and four had controlled diabetes
mellitus; one had chronic lymphocytic leukemia (CLL) that was controlled with no medication
(Table 1). Eight patients, with an average of 72.2 ± 12.2 years, were judged to be immunocompromised.
Of these, two were organ transplant recipients, and two had lymphoma being treated
with chemotherapy; the remaining patients were receiving immunosuppression for a variety
of autoimmune disorders (Table 2). Sixteen HIV-infected patients with CMVR were selected for comparison because the
diagnosis had been confirmed with PCR, and they were contemporaneous (2000–2005) with
the non-HIV-infected patients. Average age was 40.3 ± 11.6 years.

Males accounted for approximately 70% of the patients in each group (P = 0.56). None of the immunocompetent patients had bilateral disease (0%), but 4 of
the 8 (50%) immunocompromised non-HIV-patients had bilateral disease, as well as 4
of the 16 (25%) HIV-infected patients (P = 0.6). Profound, permanent vision loss worse than 20/400 occurred in 8 of the 19
eyes in the elderly, and 10 of the 20 eyes in the HIV-infected (P = 0.14). In the eight cases of profound vision loss in the elderly, five were due
to arteriolar occlusion, two to CMVR; one other case had both prior vein occlusion
and extensive retinitis. Among HIV-infected patients, vision loss was attributable
to arteriolar occlusion in only one case (P < 0.001). The remaining vision loss was due to retinal detachment or to CMVR.

More arteriolar occlusions occurred in the eyes of the elderly, immunocompetent patients
than in those of elderly, immunocompromised patients (5 of 7 (71%) vs. 1 of 12 eyes
(8%)), P = 0.07. When arteriolar occlusions in non-HIV-infected patients were compared to
HIV-infected, the results were highly statistically significant (6 of 19 eyes (32%)
vs. 1 of 20 eyes (5%)), P < .001. Findings associated with ocular ischemia, such as neovascularization, rubeosis,
and vitreous hemorrhage, were also more common in non-HIV-infected patients (6 of
19 eyes (32%) vs. 4 of 20 eyes (20%)), P < 0.003.

Vasculopathic diagnoses such as cardiovascular disease and diabetes were more common
in the elderly, especially those who were not considered to be otherwise immunocompromised
(Tables 1 and 2). Compared to HIV-infected patients, vasculopathy was present in 10 of the 15 patients
(67%) vs. 1 of 20 (5%), P < 0.001. Retinal detachment was more common in eyes in HIV-infected patients than
in non-HIV-infected patients (7 vs. 2, P = 0.03). Table 3 lists the medical and surgical interventions, and visual and anatomic outcomes.

Case reports

Case 1

A 71-year-old Indian man with hypertension and diabetes had blurred vision in the
right eye for 3 months. Vision was 20/40+ in the right eye; iritis and vitreous inflammation
were present. Peripapillary and macular cotton-wool spots were noted and there was
peripheral nonperfusion with scattered intraretinal hemorrhages temporally in the
right eye. Diabetic retinopathy was not present. The left eye was normal.

Fluorescein angiography at that time showed intact choroidal filling and delayed filling
of the arteriolar vasculature in the right eye with incomplete filling in the midperiphery.
Subtenon triamcinolone injection was given elsewhere to treat the inflammation. Toxoplasmosis
IgM and IgG antibodies, hepatitis B and C antibodies, serum immunoelectrophoresis,
antidouble-stranded DNA, hemoglobin A1C, and antinuclear antibody were negative or
normal. Serum herpes simplex virus (HSV) 1 and 2 IgG were highly positive.

Two months later on referral, visual acuity in the right eye was 5/200 with eccentric
fixation. There was 3+ anterior chamber cell and 1+ flare with small keratic precipitates
and 3+ vitreous cell with moderate haze. Intraocular pressure was 19 mmHg. Prominent
optic nerve neovascularization was noted, and arterioles appeared sclerotic and sheathed.
Dispersed intraretinal hemorrhages and a few cotton wool patches were present in the
posterior pole. Repeat FA showed lack of perfusion in the area of retinal infiltration
and extensive closure of the central retinal vasculature with macular nonperfusion
(Figure 1). Nummular retinal infiltrates were seen in the superonasal quadrant, extending from
the equator to the periphery (Figure 2).

Figure 1.Case 1, posterior fundus, right eye. Left frame: there are sclerotic central vessels and cotton-wool spots located inferotemporal
to the optic disc and fovea. Hemorrhages are located along the superior and inferior
vascular arcades. Right frame: late-phase fluorescein angiography shows minimal retrograde
filling from the optic nerve circulation of the retinal vasculature with late intraretinal
staining around the optic nerve. There is extensive capillary nonperfusion peripherally.

Figure 2.Case 1, superonasal retina, right eye. There are nummular patches of a granular necrotizing retinitis. A sclerotic arteriole
enters the area. There are scattered intraretinal hemorrhages proximal to the optic
nerve head.

Three months later, the retinitis remained active. Vision was bare light perception,
and the retinal circulation appeared more occluded. Diagnostic pars plana vitrectomy
with retinal biopsy, membrane peel, and endolaser, and C3F8 intraocular gas tamponade was performed. PCR of vitreous fluid was again positive
for CMV DNA and negative for HSV, VZV, toxoplasmosis, and Epstein-Barr virus. Retinal
biopsy showed cytomegalic inclusion bodies and CMV by immunohistochemistry (Figure 3). At surgery, the nummular lesions appeared as multiple, intraretinal, white snowflake
opacities with adhesion to the underlying RPE. No bleeding occurred during retinal
incision. All retinal arteries were sclerotic, with a crystalline appearance, and
the optic nerve head was completely atrophic. On final follow-up, the patient had
a visual acuity of light perception in his right eye with neovascularization of the
iris, ectropion uveae, and dense vitreous hemorrhage despite endolaser at surgery.

Case 2

An 81-year-old white man experienced decreased vision and redness in his right eye
that worsened over 3 weeks. Past medical history was significant for multiple sclerosis
in 1950 with bilateral optic neuritis in remission, cerebrovascular accident in 2000,
hyperlipidemia, and diabetes. Granulomatous anterior segment inflammation and a central
retinal artery occlusion of the right eye were noted by an outside ophthalmologist.
Serum CMV IgG antibody and varicella zoster antibody were positive. CMV IgM antibody,
HSV I and II IgG antibodies, and syphilis antibody were negative. Carotid artery stenosis
was 70% to 80% on the right and 50% on the left on carotid Doppler ultrasound. Varicella-related
necrotizing retinitis was suspected, and famciclovir 500 mg three times daily was
initiated.

On referral 2 months after onset, vision was counting fingers at 6 feet in the right
eye and 20/20 in the left eye with a 2+ relative afferent pupillary defect in the
right eye. There were large white keratic precipitates on the right corneal endothelium,
2+ anterior chamber cell, and 1+ flare. On dilated examination of the right eye, the
optic nerve was pale, with sclerotic, attenuated arterioles, segmentation of the venous
blood columns, and no evidence of recanalization (Figure 4). There was a patchy, granular retinitis in the inferotemporal quadrant. The diagnosis
of necrotizing retinitis with central retinal artery occlusion was made. The left
eye was free of inflammation.

Figure 4.Case 2, posterior fundus, right eye. Left frame: 5 weeks after vision loss from central retinal artery occlusion, there
is no recanalization of the artery. The venous blood columns are segmented with a
few intraretinal hemorrhages. Retinitis is barely visible inferotemporal to the macula.
Right frame: the inferotemporal periphery shows nummular lesions of a granular retinitis
similar to Case 1. The vascular closure is generalized rather than specific to the
area of retinitis.

Diagnostic AC paracentesis for PCR for CMV, varicella zoster virus, and herpes simplex
virus was positive for CMV DNA only. HIV serology was negative. An intravitreal injection
of foscarnet was given and oral valganciclovir was started. Three months later, there
was florid neovascularization of the iris. The retinitis was inactive. Bevacizumab
was injected intracamerally, and PRP was performed with regression of the NVI. Vision
remained stable at hand motions. Valganciclovir was continued at 450 mg daily adjusted
for renal function to complete 3 months of treatment.

Case 3

A 66-year-old white man presented with 3 weeks of blurred vision and floaters in his
left eye. Past medical history was significant for chronic open angle glaucoma and
CLL status post chemotherapy, with last treatment 1.5 years prior. The patient denied
pain, redness, or photophobia. Vision was 20/20- in the right eye and 20/30 in the
left eye. The intraocular pressure was 20 mmHg in the right eye and 26 mmHg in the
left eye. Slit lamp exam showed 2+ flare with rare cells and fine keratic precipitates
in the left eye. Fundus examination on the left revealed 2+ vitreous cells. There
was a small patch of chorioretinitis present in the superotemporal periphery. A presumptive
diagnosis of toxoplasmosis chorioretinitis was made. Clarithromycin and atovaquone
were started; laboratory studies included complete blood count with differential,
complete metabolic profile, rheumatoid factor, ANCA, RPR, lyme antibodies, HLA-B27,
and angiotensin converting enzyme. CBC was remarkable with 63,300 WBC with 92.4% lymphocytes.
All other laboratory studies were within normal limits; HLA-B27 antigen was present.
Subsequent toxoplasmosis IgG was positive, with a negative IgM.

After 1 week, the retinitis appeared to resolve, but one month later, vision dropped
to 20/200. Intraocular pressure was 32 mmHg with 1+ anterior chamber cell and flare
and 2+ vitreous cells. Fundus examination showed extensive arteriolar closure with
segmentation of the venous circulation confirmed by fluorescein angiography (Figure 5). The focus of chorioretinitis superotemporally had enlarged slightly (Figure 6, left). Diagnostic vitrectomy was performed 2 days later; vision prior to surgery
had declined to 6/200 ‘E’. The vitrectomy was combined with trabeculectomy with mitomycin
C. Vitreous fluid was sent for PCR analysis for CMV, HSV 1 and 2, and VZV DNA, as
well as toxoplasma IgG, flow cytometry and cytology, and viral culture. All of these
tests were negative.

Figure 5.Case 3, posterior fundus, left eye. Left frame: the vasculature is perfused centrally but there are sheathed arterioles
and intraretinal hemorrhages. Right frame: arteries and veins are truncated with extensive
capillary nonperfusion in the macula.

Figure 6.Case 3, fundus, left eye. Left frame: a single small focus of a granular necrotizing retinitis was present in
the superotemporal retina at the time of central retinal artery occlusion. Right frame:
typical CMV retinitis developed several weeks later after discontinuation of systemic
anti-viral therapy with oral ganciclovir.

Empiric valacyclovir was started. The retinal vessels appeared attenuated with macular
ischemic whitening consistent with central retinal artery occlusion. Two weeks later,
vision declined to 3/200 ‘E’. Anterior chamber paracentesis was performed, and CMV
DNA was detected by PCR. Intravenous ganciclovir was started 300 mg every 12 h for
14 days followed by oral ganciclovir 1 gram three times daily. Within 2 months, the
retinitis appeared healed; however, neovascular glaucoma developed requiring Baerveldt
glaucoma drainage implant. The intraocular inflammation and retinitis reactivated,
with focal nummular white lesions encroaching on the superior arcade. No further therapeutic
intervention was recommended due to poor visual prognosis, and the retinitis eventually
progressed to involve most of the periphery (Figure 6, right).

Discussion

The pathogenesis of CMVR likely involves hematogenous dissemination with initial infection
of the vascular endothelium and subsequent spread into adjacent tissues [5]. In HIV infection, breakdown of the blood-retinal barrier by HIV retinopathy [6] may facilitate viral spread into the retinal tissue. Pro-inflammatory cytokines may
contribute to the vasculopathic effects of the virus [7] with expression of endothelial adhesion molecules, leading to increased platelet
and leukocyte adhesion, induction of anti-phospholipid antibodies, and enhanced factor
VIII synthesis and secretion [7].

CMVR and HIV-related branch retinal artery occlusions have been rarely reported [8,9]. There have also been a few case reports of retinal vascular occlusion in HIV/AIDS
patients without CMVR [10-15]. In the five cases of ARN-like CMVR in immunocompetent patients reported in the literature
[2,3,16,17], one had branch retinal artery occlusion [14]. Designation of patients as immunocompetent or immunocompromised is imprecise even
when special testing of the immune system is performed. The elderly patients we deemed
immunocompetent were not receiving immunosuppression for organ transplantation or
chemotherapy for cancer, which are the usual causes for CMVR in non-HIV patients.
They were elderly with associated co-morbidities and, therefore, in a gray zone of
immunocompetency. They represent a large population at risk for CMVR with few apparent
risk factors other than advanced age.

Well-established risk factors for vascular occlusion were present in our patients
including hypertension, increased white blood cell counts, uncontrolled glaucoma,
giant cell arteritis, cardiovascular disease, and carotid stenosis [18]. CMV infection has been associated with atherosclerosis and with impaired circulation
[19,20]. Vascular occlusion contributed to poor visual acuity outcomes independent of macular
involvement or retinal detachment, which are the usual means by which patients with
CMVR lose vision but were not present in these patients. A weaker than normal immune
system in these elderly patients that allowed for CMVR combined with a sufficient
immune response to damage and close vessels moderately impaired by other vasculopathies
may have produced this unique presentation. In cases 1 and 4, the early use of corticosteroids
without antiviral cover before the diagnosis of CMVR was made may have allowed sufficient
worsening to permit this unusual constellation of findings.

Extensive vascular occlusion occurred when the retinal surface area involved with
retinitis was still quite small. Although risk factors for vascular closure were present,
the artery occlusions were not typical for embolic disease, for example, typical cherry-red
spots and recanalization did not occur. Despite extensive occlusions as in cases 1
and 3, at least some portion of the central retinal circulation remained patent until
late in the course. The process therefore was more likely progressive nonperfusion
that finally affected the central vasculature rather than an acute event such as a
central retinal artery occlusion. The incremental closure of the total retinal circulation
may have led to other atypical features such as the high frequency of secondary neovascularization,
which is unusual in central retinal artery occlusion and also unusual in eyes of patients
with CMVR involving the entire retina.

Conclusion

Retinal artery occlusion can occur in conjunction with CMVR in elderly, immunocompetent
patients. Recognition of CMV as a rare cause of necrotizing retinitis and institution
of early antiviral treatment may reduce the risk of this devastating complication.
Since generalized vascular occlusion is an uncommon manifestation of CMVR, older age,
concurrent illnesses, and relatively intact immune defenses with intravascular inflammation
may have contributed to this devastating outcome.

Methods

Patient lists were searched to identify non-HIV-infected patients with CMVR from 2000–2007.
Medical records were retrospectively reviewed for age and sex; medical status including
iatrogenic immunosuppression; ocular characteristics including extent of retinitis,
vascular occlusions, neovascularization, and hemorrhage; clinical estimate of grade
of inflammation; clinical course including timing of vascular occlusion relative to
onset of symptoms; results of diagnostic studies; medical treatment and response to
medication; surgical interventions; and visual outcomes. Narrative accounts of three
cases considered to be immunocompetent who developed retinal arteriolar occlusion
were created. Control patients were selected from a group of HIV-infected patients
with CMVR confirmed by polymerase chain reaction (PCR) testing and previously reported
from this institution [21].

Paired McNemar statistics were used to compare the presence and absence of bilateral
disease, profound vision loss, arteriolar occlusion, neovascularization or vitreous
hemorrhage, and retinal detachment between the non-HIV-infected and HIV-infected patients.
Small sample size hampered comparisons between the elderly, immunocompromised and
elderly, immunocompetent groups, and the elderly, immunocompetent and HIV-infected
groups. Expedited approval for retrospective review of medical records was granted
by the Human Subjects Review Board by the University of Miami Miller School of Medicine
with waiver of HIPAA authorization.

Competing interest

The authors declare that they have no competing interests.

Authors’ contributions

JLD conceived of the study, provided patients, performed the statistical analysis,
and wrote the final manuscript. PH and KH provided patients and drafted the manuscript.
All authors read and approved the final manuscript.

Authors’ information

The authors presented this study at the Joint Meeting Retina Society, Macula Society,
American Society of Retina Specialists, New York, NY on October 2, 2009. KH and PH
participated in the study while in residency training at Bascom Palmer Eye Institute
and are now practicing ophthalmologists.

Acknowledgments

None of the authors have a proprietary interest in the subject of this manuscript.
This study is supported by NIH Center grant 030-Ey14801 and by an unrestricted grant
to the University of Miami from Research to Prevent Blindness, Inc. unrestricted departmental
funds granted by the Research to Prevent Blindness, New York, NY, USA.